The impact of sarcopenia on the incidence of postoperative outcomes following spine surgery: Systematic review and meta-analysis

Purpose Sarcopenia is considered to be an important predictor of adverse outcomes following spinal surgery, but the specific relationship between the two is not clear. The purpose of this meta-analysis is to systematically review all relevant studies to evaluate the impact of sarcopenia on spinal surgery outcomes. Methods We systematically searched PubMed, Embase and the Cochrane Library for relevant articles published on or before January 9, 2023. The pooled odds ratio (OR) with 95% confidence intervals (CIs) was calculated in a random effects meta-analysis. The main outcome was the risk of adverse outcomes after spinal surgery, including adverse events and mortality. This systematic review and meta-analysis was conducted following the PRISMA guidelines to evaluate the impact of sarcopenia on spinal surgery outcomes. In addition, we also conducted a subgroup analysis and leave-one-out sensitivity analyses to explore the main sources of heterogeneity and the stability of the results. Results Twenty-four cohort studies, with a total of 243,453 participants, met the inclusion criteria. The meta-analysis showed that sarcopenia was significantly associated with adverse events (OR 1.63, 95% CI 1.17–2.27, P < 0.001) but was no significantly associated with mortality (OR 1.17, 95% CI 0.93–1.46, P = 0.180), infection (OR 2.24, 95% CI 0.95–5.26, P < 0.001), 30-day reoperation (OR 1.47, 95% CI 0.92–2.36, P = 0.413), deep vein thrombosis (OR 1.78, 95% CI 0.69–4.61, P = 0.234), postoperative home discharge (OR 0.60, 95% CI 0.26–1.37, P = 0.002) and blood transfusion (OR 3.28, 95% CI 0.74–14.64, P = 0.015). Conclusion The current meta-analysis showed that patients with sarcopenia have an increased risk of adverse events and mortality after spinal surgery. However, these results must be carefully interpreted because the number of studies included is small and the studies are significantly different. These findings may help to increase the clinicians’ awareness of the risks concerning patients with sarcopenia to improve their prognosis.


Introduction
Sarcopenia is a skeletal muscle disease that progresses with age and involves accelerated loss of muscle mass and function, including osteoporosis, fall proneness, weakness, dysfunction and death [1].The occurrence of sarcopenia is related not only to age but also to a series of longterm diseases.Its causes mainly include muscle anabolism disorder, inflammation, malnutrition, insulin resistance, mitochondrial dysfunction, oxidative stress and so on [2].Clinical data show that sarcopenia is associated with a higher incidence of postoperative complications, reoperation, longer hospital stay, and perioperative morbidity and mortality [3][4][5][6].It usually occurs during the life course of elderly individuals.
In recent years, due to COVID-19 and the increase in the proportion of aging adults worldwide, the prevalence of sarcopenia has increased [7].Concurrently, there has been an increased frequency of combined cases of spinal disease and sarcopenia.Spinal diseases primarily affect the elderly population and can result in trunk and/or limb pain, paralysis, and/or deformities, ultimately disrupting their motor function.Spinal surgery is a common treatment for most spinal diseases [8], and the factors affecting its prognosis have always been one of the main research directions of spinal surgery.Studies have shown that sarcopenia has been increasingly recognized as an important predictive factor for adverse outcomes following complex spinal surgery [9].Therefore, there is a need for further analysis and evaluation of the predictive value of sarcopenia for adverse postoperative outcomes of spinal surgery to enable clinical practitioners to identify patients at risk of experiencing adverse outcomes following spinal surgery and implement early interventions to reduce the incidence of postoperative adverse events.
An increasing number of studies have begun to focus on the effects of sarcopenia on spinal surgery patients.Zakaria, H.M. et al. found that sarcopenia can predict postoperative mortality, adverse events and infection in patients with spinal metastases who undergo thoracolumbar revision surgery [4,5].In addition, Hirase, T. et al. reported that sarcopenia can also predict the incidence of deep venous thrombosis in thoracolumbar revision surgery patients [5].However, some studies have found different conclusions.Barile, F. et al. found that there was no significant correlation between sarcopenia and the incidence of infection and adverse events after posterior lumbar fusion [10].Furthermore, the study by Brinkmann, E. J. et al. showed that in patients with spinal tumors, there was no significant correlation between sarcopenia and mortality, infection or reoperation after tumor resection [11].
Flexman, A. M. et al. found an unreliable correlation between sarcopenia and adverse health outcomes [2] that may have resulted from differences in the definition of sarcopenia and methods for measuring postoperative outcomes.In addition, the study population and the type of surgery may also be factors that affect the prediction of the incidence of adverse events after spinal surgery [9].Understanding the importance and relevance of sarcopenia as a risk factor for patients undergoing spinal surgery, as well as better assessing the risk of having a poor prognosis, will help surgeons to optimize treatment.To solve this problem, we conducted this meta-analysis.This meta-analysis systematically reviews previous related studies to evaluate the impact of sarcopenia on the outcome of spinal surgery.

Standard protocol approvals, registrations, and patient consent
This study was conducted and reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocol (PRISMA-P) guidelines [12] and the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) guidelines [13].The protocol was registered on the website https://www.crd.york.ac.uk/prospero/(Registration number: CRD42023406667).

Data sources and search strategy
Two independent investigators systematically searched PubMed, Embase and the Cochrane Library from database inception to January 9, 2023, without any language or publication time limitations.We used medical subject headings (MeSH) in our search of PubMed and the Cochrane Library and Embase subject headings (Emtree) in our search of Embase, in addition to free-text words (including closely related words or synonyms) related to spinal surgery, sarcopenia and postoperative complications.The search strategy used the following terms: ("Laminectomy" or "Spin*/surgery" or "Spinal Fusion" or "Spinal Cord Diseases/surgery" or "Laminoplasty" or "Diskectomy" or "Kyphoplasty" or "Cementoplasty" or "Spinal Fractur*" or "Spinal Injur*" or "Spinal Cord Injuries" or "Vertebroplasty" or "Foraminotomy") and ("Sarcopenia" or "Muscular Atrophy" or "Muscle Hypotonia" or "Dystonia" or "Muscle, Skeletal/ abnormalities" or "Muscular Disorders, Atrophic" or "Muscle Weakness" or "Muscle Strength" or "Physical Fitness" or "Geriatric Assessment") (eTable 1 in S1 File).Additionally, we manually searched the reference list of previous systematic reviews and meta-analyses for missing papers.When the same cohort was described in multiple articles, only the most recent article or the article that included the largest number of participants was included.
Citations from the initial search were downloaded and merged by using Endnote X9 software, and duplicate records were identified and manually deleted.In accordance with the PICOS guidelines, six investigators independently reviewed the titles and abstracts to identify studies eligible for inclusion.In the event of disagreement, the final decision was made through consultation with two senior reviewers.

Study selection
Potential studies were considered eligible for inclusion if they met the following preestablished inclusion/exclusion criteria: 1. Participant: patients �18 years of age who underwent spinal surgery.
4. Outcome: Adverse events and mortality were the primary outcomes, while other complications (postoperative infection, reoperation, deep venous thrombosis, blood transfusion, readmission) were the secondary outcomes.The effect size was presented as the odds ratio (OR) and 95% confidence interval (CI).

Study design:
A prospective or retrospective cohort study.
We excluded conference papers, reported individual cases and systematic reviews, or studies that did not provide sufficient data.

Data extraction
Two researchers used a predesigned spreadsheet to extract data from each included study.Disagreements between reviewers were resolved through discussion or consultation with a third reviewer.The following data were extracted: first author, publication year, types of study, age, average body mass index (BMI), geographic regions, follow-up, sample size, percentage of women, type and site of operation, definitions and measurements of sarcopenia, outcomes, reported OR and adjusted variables.

Methodological quality assessment
Two authors independently assessed the methodological quality of each qualified study using the Newcastle-Ottawa Scale (NOS) [14].The scale covers three domains, including patient representativeness, exposure and outcome determination, and follow-up adequacy.The total score for each study was 9. A score � 8 indicates high quality (low bias risk) [15].

Statistical analysis
All analyses were conducted using Stata statistical software (version 12.0; Stata, University Station, Texas, USA).Considering the heterogeneity between patient baselines, a fixed-effect model was used [16].A fully adjusted effect estimate (OR) of the correlation between sarcopenia and the surgical outcomes was used to derive pooled risk estimates described in a forest plot.Heterogeneity between studies was evaluated by the Cochrane Q test and I 2 statistic.When I 2 � 50% or P < 0.05, heterogeneity was determined to be statistically significant [16].To explore the source of heterogeneity in the study, we performed a series of subgroup analyses according to geographical regions (China, USA, and other areas), sample sizes (�100 individuals, 100-200 individuals or �200 individuals), average age (�65 years, 65-70 years, �70 years), average BMI (18.5-24.9kg/m 2 , 25-29.9 kg/m 2 , �30 kg/m 2 ), sex (male or female), measurement of sarcopenia (NTPA, SMI or other methods), follow-up period (�12 months, >12 months), type of surgery (thoracic or lumbar spine) and the quality of the study (low or high).The symmetry of the funnel chart was evaluated visually and combined with Begg's and Egger's tests to evaluate publication bias.Begg's and Egger's tests and visual examination of funnel plot asymmetry were used to evaluate publication bias.We used Duvall & Tweedie's trim-and-fill method to further adjust the risk estimate to assess the potential impact of publication bias [17].Sensitivity analysis was performed by excluding each study to evaluate the stability of the results.For all statistical tests, a P value < 0.05 was considered statistically significant.

Literature search
A preliminary search yielded 80,821 records and an additional 4 records from other sources.After removing duplicates (n = 2,488), 78,337 titles and abstracts were screened.Of these, 56 articles were selected for full-text review according to the title or abstract.Based on the aforementioned inclusion and exclusion criteria, 32 studies were excluded, leaving 24 studies for inclusion in this meta-analysis (Fig 1).

Characteristics of studies
Table 1 shows the baseline characteristics of the included studies.The studies included in this review were published between 2015 and 2023, with 70.83% of the studies [3-6, 10, 11, 18-28] published in 2020 or later.Of the 24 studies, 9 studies [3-6, 11, 24, 25, 29, 30] were conducted in the United States, 4 studies [4,[18][19][20] were conducted in China, and 83.33% (20/24) of the studies included in the analysis were high-quality studies with NOS scores of 8 or higher (Table 2).The total sample size of the study was 243,453, the average sample size was 10,144, and the average follow-up time was 23.79 months (range, 3-72 months).Four studies used the skeletal muscle index (SMI) to measure sarcopenia with respect to the measurement standard of muscular dystrophy [18,20,26,31], three studies used the psoas lumbar vertebral index (PLVI) [10,11,23], and three studies used the total psoas area/vertebral body area (TPA/VBA) [5,22,32].Our meta-analysis included 2 prospective studies and 22 retrospective studies.The remaining studies measured and assessed sarcopenia using MRI, CT, or working group measurement standards.
Subgroup analyses showed that the risk was significantly increased in the subgroups of studies with a female proportion of 50-60%, conducted in China, those focusing on lumbar surgery, average age�65years and average BMI�30 kg/m 2 .Additionally, the analysis did not show a significant correlation between sarcopenia and the risk of postoperative complications in subgroups stratified by sample size, sarcopenia measurement methods, average follow-up time, and quality rating.By conducting subgroup analysis stratified by study region, sample size, average age, average BMI, sex, methods for measuring sarcopenia, mean follow-up time, and type of surgery, we found a significant reduction in heterogeneity, indicating that the heterogeneity can be attributed to these variables (Table 3).
We use sensitivity analysis to analyze the stability of the results.During the analysis, we found that the combined OR did not change significantly due to any individual study (lowest OR = 1.38, 95% CI 1.05-1.80,highest OR = 1.81, 95% CI 1.15-2.85).Visual inspection of the funnel plot showed basic symmetry (Fig 3), which was further validated by Egger's test (P = 0.199) and Begg's test (P = 0.917), indicating no publication bias.
Subgroup analyses showed a significantly increased risk in the subgroups with a sample size �200.Furthermore, subgroup analyses of studies conducted in the USA or elsewhere, sex, average age, average BMI, sarcopenia measurement methods, average follow-up time, and quality evaluation did not show a significant association between sarcopenia and postoperative  mortality.Heterogeneity was significantly reduced in subgroup analyses of average age, sex and quality evaluation, suggesting that heterogeneity might have originated from these variables (Table 4).Through sensitivity analysis, we found that the combined OR did not change significantly for any individual study (lowest OR = 1.09, 0.87-1.36,highest OR = 1.21, 0.95-1.53).Gross examination of the funnel plot revealed basic symmetry and potential evidence of publication bias (Fig 5), as demonstrated by Begg's test (P = 0.260) and Egger's test (P = 0.189).We performed Duvall & Tweedie's trim and fill method as adjustments to risk estimates to assess the potential effects of publication bias.The results revealed one potentially missing study in the funnel plot region, with an OR value of 1.128 (95% CI 0.877-1.452)after publication bias adjustment, which was similar to the preliminary results.

Principal findings
This meta-analysis systematically reviewed data from 24 cohort studies and analyzed the relationship between sarcopenia and other postoperative outcomes of spinal surgery.Our metaanalysis found a significant correlation between sarcopenia and the risks of postoperative adverse events and mortality.However, we did not find a significant correlation between sarcopenia and the risks of infection, 30-day reoperation, deep vein thrombosis, return home after surgery, or blood transfusion.

Potential mechanisms
The increase in the incidence of adverse events after spinal surgery in patients with sarcopenia is attributable to a decrease in protein reserves, disruption of muscle protein homeostasis leading to a decrease in muscle mass, and an increase in systemic inflammation [34,35].Li Ziquan et al. found that the mechanism of poor prognosis in patients with sarcopenia was multifactorial, including muscle protein homeostasis imbalance, reduced reserves to respond to stress stressful events, and an enhanced systemic inflammatory response [20,36,37].The investigation found that there are many muscle tissue factors that regulate bone tissue activity, and sarcopenia can affect various regulatory factors related to bone remodeling, such as insulin-like growth factor (IGF-1), fibroblast growth factor (FGF-2), interleukins (IL-6, IL-15), myostatin, bone glycine, and irisin.Therefore, sarcopenia is related to a decrease in bone density [38][39][40].A reduced bone mineral density is an important factor influencing the occurrences of falls and fractures and may also be a factor that contributes to an increase in the incidence of postoperative adverse events.In addition, sarcopenia is associated with hormonal imbalances and increased cytokine activity, which can lead to physical decline [38][39][40][41], and it may be related to an increase in the incidence of adverse events and mortality in patients after surgery.Zakaria, H.M. et al. found that sarcopenia may reflect the "cachexia" phenotype, which is a result of metabolic abnormalities in patients with advanced cancer and a potential cause of increased mortality after spinal surgery in sarcopenia patients [4,42,43].
A study found that the level of Runx2, a transcription factor essential to osteocyte maturation in patients with sarcopenia, was decreased, which was associated with a decrease in bone mineral density [44].According to Mechanostat theory, the direct mechanical stimulation of bone caused by muscle contraction can promote osteogenesis, but this part of stimulation is lacking in sarcopenia patients [45].In addition, sarcopenia and osteoporosis share many common pathways, such as sensitivity to decreased secretion of anabolic hormones, increased activity of inflammatory cytokines, and release of anabolic or catabolic molecules (muscle factors and bone factors) from skeletal muscle or osteocytes, resulting in reduced physical activity [46][47][48].In the Ma et al study, it is found that muscle can affect bone mineral density through some physical mechanisms or the release of biological factors, and lean body weight may be a factor affecting bone mineral density [45].To sum up, sarcopenia is likely to be a factor leading to the decrease of bone mineral density.In addition, there is growing evidence that bones and muscles can secrete various cytokines that regulate each other, including myostatin, irisin, interleukin 6, osteocalcin, RANKL, and osteoprotegerin [49].In patients with sarcopenia, the reduced muscle activity may lead to relatively inadequate secretion of certain cytokines or hormones vital for metabolism and muscle function.These hormones play an important role in the human body, and the relative deficiency of these important hormones may be an important cause of adverse events after spinal surgery in patients with sarcopenia.

Comparison with other studies
When investigating the relationship between sarcopenia and mortality after spinal surgery, we found three similar systematic reviews [9,50,51], all of which indicated an increased risks of sarcopenia and mortality after spinal surgery.However, two of them did not find a significant correlation between sarcopenia and the incidence of adverse events after spinal surgery [9,51].In addition, the above studies have certain limitations due to reporting bias, insufficient subgroup analysis, inconsistent measurement standards for sarcopenia, etc.We used Duvall & Tweedie's pruning and filling methods to adjust the risk estimates to evaluate the potential impact of publication bias and conducted a series of subgroup analyses to explore the heterogeneity of the study.This study is currently the largest and most comprehensive study investigating the relationship between sarcopenia and different outcomes after spinal surgery for nearly 240,000 participants.

Implications
In this study, the approximate risk of various complications after spinal surgery are estimated in patients with sarcopenia to provide guide future clinical practice.Preoperative measurement and effective management of skeletal muscle mass in patients have important clinical significance in preventing postoperative death and adverse events.At present, clinical doctors do not realize the importance of managing sarcopenia before spinal surgery and thus have not established standardized treatment for sarcopenia patients before surgery.This study provides new evidence-based medical evidence for clinical doctors to treat such patients.For patients with sarcopenia, providing appropriate and effective treatment before surgery will help to reduce the occurrence of postoperative complications.

Strengths
The current meta-analysis has the following strengths.First, we comprehensively searched the literature in three major databases, PubMed, Cochrane Library, and Embase, using MeSH/  Emtree and free text terms and developed a comprehensive database search strategy that was not limited by date or language.As a result, we found original articles that met the inclusion criteria to avoid publication bias and improve the reproducibility of the results.Second, we adhered to the PRISMA guidelines and used the NOS scale to provide complete, informative, and transparent scoring criteria for the included studies.Third, we used several methods to fully test the stability of the results, including sensitivity analysis and subgroup analysis.Finally, by using the trim-and-fill method to adjust the summary estimation based on publication bias, we found that the results were consistent with the initial results.

Limitations
Our research still presents some potential limitations.First, we found that there was some interstudy heterogeneity in the occurrences of postoperative mortality and adverse events, possibly due to a lack of standardization in the measurement of sarcopenia and differences in the baseline characteristics of the study cohort.However, we conducted further analysis to evaluate the source of this heterogeneity, and the adjusted results were consistent with the initial results.The subgroup analysis found that interstudy heterogeneity had little impact on the final results.Second, our conclusions were based on the data of a retrospective cohort study, so we cannot infer the causal relationship between sarcopenia and the incidences of adverse events and mortality after spinal surgery, which is also an inherent limitation of meta-analyses.Third, we also found that the impact of some risk factors was estimated near the border, with a confidence interval between 0.95 and 5.26 (such as infection).These findings need to be verified in a large prospective cohort study.Finally, at present, the diagnosis of sarcopenia is not unified, and there are no restrictions on the diagnosis of sarcopenia in our study.There are some differences between the different diagnostic methods of sarcopenia among the included studies, and these differences will affect our correct evaluation of the impact of sarcopenia on spinal surgery.

Conclusions
The current meta-analysis showed that patients with sarcopenia have increased risks of adverse events and mortality after spinal surgery.However, these results must be carefully interpreted because the number of studies included is small and the studies are significantly different.These findings may help to increase the clinicians' awareness of the risks that are concerns patients with sarcopenia to improve their prognosis.

P
(Population): Patients �18 years of age undergoing spinal surgery I (Intervention): Patients diagnosed with sarcopenia C (Comparison): Patients not diagnosed with sarcopenia O (Outcome): Postoperative outcomes such as adverse events and mortality